Growing New Limbs the Zebrafish Way

A zebrafish tail fin one day after amputation is shown on the left. The image on the right shows that by ten days post amputation, the tail fin has regenerated.

 

A lost tail fin can really slow down a zebrafish - at least for a week or so, until it grows a new one. Now scientists have shown that they can turn on or block this regeneration in zebrafish with the flip of a molecular switch. Understanding how the fish's cells coordinate the regrowth of the structurally complex fin can help scientists understand the process of regeneration, providing clues that may aid in the development of new clinical therapies, such as renewing cardiac tissue after heart disease.

 

The scientists said that not only will their findings advance research aimed at regenerating tissues and organs, but the discoveries could also lead to improved therapies for bone marrow transplants to restore the hematopoetic system in cancer patients.

"In studying injury or inflammation in any context, investigators should explore whether Wnt signaling is involved. These experiments suggest that Wnt signaling is a universal component of regenerative pathways in animals."
Randall T. Moon 

 

The researchers' findings were published online December 22, 2006, as a Development ePress article, which is posted in advance of print publication in the journal Development. The senior author was Howard Hughes Medical Institute investigator Randall Moon at the Institute for Stem Cell and Regenerative Medicine of the University of Washington School of Medicine, and the joint first authors were Cristi Stoick-Cooper and Gilbert Weidinger, who designed and carried out the experiments in the Moon laboratory.

 

Using tail fin regeneration in the zebrafish as a model system, the researchers discovered that a major cellular signaling pathway, called the Wnt/ß-catenin pathway, is central to activating the complex machinery of limb regeneration. This pathway is known to play a major role in regulating stem cells in embryonic development and adult tissue maintenance. Malfunctions in the pathway have been proven to lead to cancers, as well as being linked to bone density diseases and neurodegenerative diseases.

 

The Wnt/ß-catenin pathway comprises a large group of proteins that are activated when the signaling molecule Wnt binds to the pathway's cell surface receptors. This activation increases the levels of ß-catenin - a master regulator of multiple genes - that reach the cell nucleus.

 

The researchers also found that a related Wnt protein, called wnt5b, inhibited regeneration. Wntb5 governs a signaling pathway that is independent of ß-catenin. So, Wnt proteins can turn on more than one signaling pathway, and both are involved in regeneration, though with opposite roles.

 

"It was previously known that Wnt pathway components were expressed during regeneration, but nobody had really explored whether the pathways were indeed activated," said Moon. "And nobody had separated the two pathways and looked at their effects individually."

 

In their experiments, Stoick-Cooper and Weidinger genetically manipulated the Wnt/ß-catenin pathway in the fish and measured how that manipulation affected the fish's ability to regrow an amputated tail fin.

 

Using a fluorescent "reporter" gene that revealed Wnt/ß-catenin pathway activation by glowing like a firefly, the scientists showed that the pathway was clearly switched on during regeneration, just in the area of the body that was regenerating. Similarly, they saw that the pathway was activated during regeneration of zebrafish heart and mouse liver, which they said suggests that the pathway may function in regeneration across species. They further noted that the Wnt/ß-catenin pathway was activated during the formation of the undifferentiated cells that proliferate to regenerate the tail fin.

 

They next genetically engineered fish in which they could switch off the Wnt/ß-catenin pathway by exposing the fish to warm water. Doing so, they found, completely blocked regeneration. They could also accelerate regeneration by enhancing Wnt/ß-catenin signaling. The researchers noted that this is a significant finding for the new field of regenerative medicine, in which a means of enhancing regeneration is an invaluable tool.

 

In contrast, when they engineered fish to activate the wnt5b gene in response to warm water, regeneration was inhibited. The opposite is true in fish with a mutation in the wnt5b gene, in which they found that regeneration was augmented. This is what one would expect, Moon noted, since the loss of a functional inhibitor is a double negative — meaning that regeneration should be accelerated.

 

"These experiments showed that there is a completely novel and unexpected mechanism that antagonizes the regenerative process," said Moon. "There had been other studies indicating that wnt5b-like genes could block the Wnt/ß-catenin pathway, but no one had examined whether this antagonism occurs in the context of the normal regenerative process."

 

"Cristi and Gilbert's experiments rigorously establish through genetic approaches that the Wnt pathways are functionally important in regeneration," he said. "More generally, they show that in studying injury or inflammation in any context, investigators should explore whether Wnt signaling is involved. These experiments suggest that Wnt signaling is a universal component of regenerative pathways in animals," he said.

 

According to Moon, the findings by Stoick-Cooper and Weidinger will have clinical implications for tissue regeneration, as well as for encouraging growth of stem cells. Stem cells are immature, undifferentiated cells that are capable of maturing into a variety of mature cell types.

 

"Wnt/ß-catenin signaling plays an important positive role in the differentiation of stem cells and progenitor cells that are required for regeneration," he said. "It agrees with previous studies in which our laboratory showed in animals that activating this pathway increases the success of transplants of blood-forming hematopoietic stem cells. Such transplants in cancer patients whose immune systems have been destroyed by radiation or chemotherapy are invaluable as therapy; and sometimes they fail because they transplanted cells do not engraft into the bone marrow. We believe that enhancing the Wnt/ß-catenin pathway will increase the success rate of such hematopoietic stem cell transplants," he said.

 

In other clinically-related studies, Moon and his colleagues are exploring whether activating the Wnt/ß-catenin pathway can enhance differentiation of human embryonic stem cells into cardiac cells that could be used to treat heart disease

 

Moon and his colleagues are also exploring how the myriad different kinds of cells involved in regeneration respond to Wnt-activating signals and, in collaboration with HHMI investigator Leonard I. Zon at Children's Hospital, Boston, how injury switches on Wnt/ß-catenin signaling. The researchers are optimistic that Wnt signaling will be an important therapeutic target in the growing field of regenerative medicine.

 

Original Article

Insuling, aging, and mass

Scientists from the new interdisciplinary LIMES (Life & Medical Sciences) Centre at the University of Bonn have identified a new gene which could play an important role in the development of diabetes. Flies in which this hereditary factor is defective are also significantly smaller than other members of their species and live appreciably longer. The gene seems to have such a crucial function that it has hardly changed in just under a billion years: it is found in flies, but in a similar form it is also found in mice and humans. In the current issue of the prestigious journal Nature the Bonn researchers have published two articles on this topic.

Sometimes science resembles a relay race: in 1996 the biochemist Professor Waldemar Kolanus discovered a group of cellular proteins, the cytohesins, and described their function in the immune system. Two of his colleagues at the LIMES Centre in Bonn have now found a totally new and completely unexpected function of these proteins which is very relevant to medicine. 'We wanted to know whether there were also cytohesins in the fruit fly drosophila and what functions they have there,' the evolutionary biologist Professor Michael Hoch reminisces. He and his team were in fact successful. They discovered a protein which is very similar to the cytohesins in mammals. Even more interestingly, fruit flies in which the genetic blueprint for this gene is defective are smaller in size. So the researchers nicknamed cytohesin 'Titch'. 'The effect on the insect's growth showed us that 'Titch' could play a key role in the metabolism of insulin – a completely new role for cytohesins,' Professor Hoch says.

New anti-aging ingredient

A new anti-aging ingredient developed by UNSW researchers is expected to be available in skin products as early as next year.

Known as GGC, it is a precursor for an effective antioxidant known as glutathione, that has a broad range of potential health benefits. Glutathione is the body's key defence for detoxifying harmful compounds implicated in cancer, diabetes, aging and other diseases and degenerative conditions.

After nine years in development, UNSW researchers Dr Wallace Bridge and Dr Martin Zarka have established a new, cost-effective process for manufacturing GGC, which has been licensed to pharmaceutical company, Biospecialties Australia. A newly-expanded manufacturing plant at Mayfield, near Newcastle, will produce GGC.

It is expected that GGC will be used as an active ingredient in foods, health care, toothpastes, dietary supplements and cosmetics as well as in skin repair anti-aging creams.

Original Article

New Observations On Properties Of Water

Recent research on the properties of water reveals information relevant for cloud physics and even cryopreservation science.

Experimental studies conducted by Ph.D. Anatoli Bogdan at the University of Helsinki, Finland, have received broad interest in the scientific world, as the results might have applications even in the cryopreservation of cells and tissues. Bogdan's results show that mixture droplets consisting of sulphuric acid and water can be slowly cooled down to-140 degrees Celsius and then heated again without ice formation. The formation of ice is particularly problematic in cryopreservation, as the crystal formation damages cell structures.

Bogdan has conducted his experiments by cooling and heating droplets of 0.5-6 µm in diameter. His study focuses on two forms of water: low-density amorphous ice (LDA, or so-called glassy water) and highly viscous water (HVW), which is a liquid phase that LDA melts into. Bogdan reports that HVW is not a new form of water as some scientists believed. Bogdan's study Reversible Formation of Glassy Water in Slowly cooling Diluted Drops has been published in Journal of Physical Chemistry in June 2006.

Bogdan himself applies his observations on the properties of water in cloud research, and he and his colleagues have recently published a study dealing with cirrus clouds (Formation of Low-Temperature Cirrus from H2SO4/H2O Aerosol Droplets, Journal of Physical Chemistry, November 2006). Their study suggests that, unlike previously thought, the cloud crystals in cirrus clouds are not completely solid ice, but are covered with a layer of liquid water and sulphuric acid. The layer effects for instance the reflectivity of the clouds, and therefore the climate. It has also been observed that the rate of ozone loss is higher on liquid than on solid surfaces. The results therefore indicate that the ozone is destroyed in the cirrus clouds faster than conventionally has been thought.

Original Article

Forsyth Scientists Discover Early Key to Regeneration

Science may be one step closer to understanding how a limb can be grown or a spinal cord can be repaired. Scientists at The Forsyth Institute have discovered that some cells have to die for regeneration to occur. This research may provide insight into mechanisms necessary for therapeutic regeneration in humans, potentially addressing tissues that are lost, damaged or non- functional as a result of genetic syndromes, birth defects, cancer, degenerative diseases, accidents, aging and organ failure. Through studies of the frog (Xenopus) tadpole, the Forsyth team examined the cellular underpinnings of regeneration.

 

The Xenopus tadpole is an ideal model for studying regeneration because it is able to re-grow a fully functioning tail and all of its components, including muscle, vasculature, skin, and spinal cord.  The Forsyth scientists studied the role that apoptosis, a process of programmed cell death in multi-cellular organisms, plays in regeneration. The research team, led by Michael Levin, Ph.D., Director of the Forsyth Center for Regenerative and Developmental Biology, found that apoptosis has a novel role in development and a critical role in regeneration. According to Dr. Levin, “Simply put, some cells have to die for regeneration to happen.”

 

The findings will be published in the January 1, 2007 issue of Developmental Biology (v301i1).  “We were surprised to see that some cells need to be removed for regeneration to proceed,” said Ai-Sun Tseng, Ph.D. the paper’s first author. “It is exciting to think that someday this process could be managed to allow medically therapeutic regeneration.”

 

Summary of Study

 

In the context of efforts to understand biophysical controls of regenerative processes, The Forsyth Center for Regenerative and Developmental Biology investigated the dynamics of cell number control in the regenerating tail bud. Previous research in the field has shown that one mechanism by which cell number is controlled is by programmed cell death, which has been shown to be involved in sculpting of growing tissue in a number of developmental systems including heart, limb and craniofacial patterning.  This study shows that despite the massive tissue proliferation required to build the tail, an early apoptotic event is required for regeneration. Normal regeneration of the tail includes a small focus of apoptotic cells; when apoptosis is inhibited during the first 24 hours, regeneration cannot proceed and the growth of nerve axons becomes abnormal. Later inhibition of apoptosis has no effect, suggesting that the programmed death of a specific cellular component is a very early step in the regeneration program. One possible model is that tissues normally contain a population of cells whose purpose is to prevent massive growth in the region surrounding them.  Future work by the Levin group will identify the cells that must die, in order to try to understand the signals that cells utilize for growth control.

 

Michael Levin, PhD. is an Associate Member of the Staff in The Forsyth Institute Department of Cytokine Biology and the Director of the Forsyth Center for Regenerative and Developmental Biology. Through experimental approaches and mathematical modeling, Dr. Levin and his team examine the processes governing large-scale pattern formation and biological information storage during animal embryogenesis.  The lab’s investigations are directed toward understanding the mechanisms of signaling between cells and tissues that allows a living system to reliably generate and maintain a complex morphology.  The Levin team studies these processes in the context of embryonic development and regeneration, with a particular focus on the biophysics of cell behavior.

 

The Forsyth Institute is the world’s leading independent organization dedicated to scientific research and education in oral, craniofacial and related biomedical sciences.

Original Article

Growing heart muscle

ANN ARBOR, Mich. — It looks, contracts and responds almost like natural heart muscle – even though it was grown in the lab. And it brings scientists another step closer to the goal of creating replacement parts for damaged human hearts, or eventually growing an entirely new heart from just a spoonful of loose heart cells.

This week, University of Michigan researchers are reporting significant progress in growing bioengineered heart muscle, or BEHM, with organized cells, capable of generating pulsating forces and reacting to stimulation more like real muscle than ever before.

The three-dimensional tissue was grown using an innovative technique that is faster than others that have been tried in recent years, but still yields tissue with significantly better properties. The approach uses a fibrin gel to support rat cardiac cells temporarily, before the fibrin breaks down as the cells organize into tissue.

The U-M team details its achievement in a new paper published online in the Journal of Biomedical Materials Research Part A.

And while BEHM is still years away from use as a human heart treatment, or as a testing ground for new cardiovascular drugs, the U-M researchers say their results should help accelerate progress toward those goals. U-M is applying for patent protection on the development and is actively looking for a corporate partner to help bring the technology to market.

Ravi K. Birla, Ph.D., of the Artificial Heart Laboratory in U-M's Section of Cardiac Surgery and the U-M Cardiovascular Center, led the research team.

"Many different approaches to growing heart muscle tissue from cells are being tried around the world, and we're pursuing several avenues in our laboratory," says Birla. "But from these results we can say that utilizing a fibrin hydrogel yields a product that is ready within a few days, that spontaneously organizes and begins to contract with a significant and measurable force, and that responds appropriately to external factors such as calcium."

The new paper actually compares two different ways of using fibrin gel as a basis for creating BEHM: layering on top of the gel, and embedding within it. In the end, the layering approach produced a more cohesive tissue that contracted with more force – a key finding because embedding has been seen as the more promising technique.

The ability to measure the forces generated by the BEHM as it contracts is crucial, Birla explains. It's made possible by a precise instrument called an optical force transducer that gives more precise readings than that used by other teams.

The measurement showed that the BEHM that had formed in just four days after a million cells were layered on fibrin gel could contract with an active force of more than 800 micro-Newtons. That's still only about half the force generated within the tissue of an actual beating heart, but it's much higher than the forces created by engineered heart tissue samples grown and reported by other researchers. Birla says the team expects to see greater forces created by BEHM in future experiments that will bathe the cells in an environment that's even more similar to the body's internal conditions.

In the new paper, the team reports that contraction forces increased when the BEHM tissues were bathed in a solution that included additional calcium and a drug that acts on beta-adrenergic receptors. Both are important to the signaling required to produce cohesive action by cells in tissue.

The U-M team also assessed the BEHM's structure and function at different stages in its development. First author and postdoctoral fellow Yen-Chih Huang, Ph.D., of the U-M Division of Biomedical Engineering, led the creation of the modeling system. Co-author and research associate Luda Khait examined the tissue using special stains that revealed the presence and concentration of the fibrin gel, and of collagen generated by the cells as they organized into tissue.

Over the course of several days, the fibrin broke down as intended, after fulfilling its role as a temporary support for the cells. This may be a key achievement for future use of BEHM as a treatment option, because the tissue could be grown and implanted relatively quickly.

The U-M Artificial Heart Laboratory (www.sitemaker.umich.edu/ahl) is part of the U-M Section of Cardiac Surgery, and draws its strength from the fact that it includes bioengineers, cell biologists and heart surgeons – a multidisciplinary group that can tackle both the technical and clinical hurdles in the field of engineering heart muscle. Its focus is to evaluate different platforms for engineering cardiovascular structures in the laboratory. Active programs include tissue engineering models for cardiac muscle, tri-leaflet valves, cell-based cardiac pumps and vascular grafts. In addition, the laboratory has expertise in several different tissue engineering platforms: self-organization strategies, biodegradable hydrogels such as fibrin, and polymeric scaffolds.

Each approach may turn out to have its own applications, says Birla, and the ability to conduct side-by-side comparisons is important. Other researchers have focused on one approach or another, but the U-M team can use its lab to test multiple approaches at once.

"Fundamentally, we're interested in creating models of the different components of the heart one by one," says Birla.

"It's like building a house – you need to build the separate pieces first. And once we understand how these models can be built in the lab, then we can work toward building a bioengineered heart." He notes that while many other labs focus on growing one heart component, only U-M is working on growing all the different heart components.

Already, the U-M team has begun experiments to transplant BEHM into the hearts of rats that have suffered heart attacks, and see if the new tissue can heal the damage. This work is being conducted by Francesco Migneco, M.D., a research fellow with the Artificial Heart Laboratory. Further studies will implement "bioreactors" that will expose the BEHM tissue to more of the nutrients and other conditions that are present in the body.

evolutionary risk of cancer based on body mass

A key enzyme that cuts short our cellular lifespan in an effort to thwart cancer has now been linked to body mass.

Until now, scientists believed that our relatively long lifespans controlled the expression of telomerase--an enzyme that can lengthen the lives of cells, but can also increase the rate of cancer.

Vera Gorbunova, assistant professor of biology at the University of Rochester, conducted a first-of-its-kind study to discover why some animals express telomerase while others, like humans, don't. The findings are reported in today's issue of Aging Cell.

"Mice express telomerase in all their cells, which helps them heal dramatically fast," says Gorbunova. "Skin lesions heal much faster in mice, and after surgery a mouse's recovery time is far shorter than a human's. It would be nice to have that healing power, but the flip side of it is runaway cell reproduction--cancer."

Up until now, scientists assumed that mice could afford to express telomerase, and thereby benefit from its curative powers, because their natural risk of developing cancer is low--they simply die before there's much likelihood of one of their cells becoming cancerous.

"Most people don't know that if you put mice in a cage so the cat can't eat them, 90 percent of them will die of cancer," says Gorbunova.

Evolution, it seems, has determined which species are allowed to express telomerase in their somatic cells in order to maintain a delicate balance between cells that live long, and cells that become cancerous. But while most scientists believed an organism's lifespan determined whether it was at a higher risk of cancer, Gorbunova has revealed evidence that it is not our long lifespan that puts us at risk, but our much-heavier-than-a-mouse body mass.

The tips of chromosomes, called telomeres, shorten every time a cell divides. After about 60 divisions, the telomeres are eroded away to the point that the cell stops dividing. Telomerase rebuilds those tips, so animals that express it, like mice, have cells that can reproduce more extensively and thus heal better. Cancer cells, however, are those cells that constantly reproduce unchecked, and so evolution has shut off the expression of telomerase in human somatic cells, presumably because the threat of cancer outweighs the benefits of quick-healing.

But no one has looked into why mice express telomerase and humans don't. In fact, telomerase activity has been barely catalogued in the animal kingdom. Gorbunova decided to take on the question by creating a unique test. She investigated 15 rodents from across the globe to determine what level of telomerase activity each species expressed, to see if there were some correlation she could find.

The species ranged from tiny field mice to the 100-pound capybara from Brazil. Lifespans ranged from three years for the mice, to 23 or more for common backyard squirrels.

Acquiring specimens of these animals from around the world proved to be an unusual task.

"At one point I was woken up at two in the morning by a guy on a cell phone hunting pest beavers in Montezuma," says Gorbunova. "I'm still trying to wake up and this voice says, 'I hear you're looking for beavers.' "

For over a year, Gorbunova collected deceased rodents from around the world and had them shipped to her lab in chilled containers. She analyzed their tissues to determine if the telomerase was fully active in them, as it was in mice, or suppressed, as it is in humans. Rodents are close to each other on the evolutionary tree and so if there were a pattern to the telomerase expression, she should be able to spot it there.

To her surprise, she found no correlation between telomerase and longevity. The great monkey wrench in that theory was the common gray squirrel, which lives an amazing two decades, yet also expresses telomerase in great quantity. Evolution clearly didn't see long life in a squirrel to be an increased risk for cancer. Body mass, however, showed a clear correlation across the 15 species. The capybara, nearly the size of a grown human, was not expressing telomerase, suggesting evolution was willing to forgo the benefits in order to reign in cancer.

The results cannot be directly related to humans, but Gorbunova set up the study to produce very strong across-the-board indicators. It's clear that evolution has found that the length of time an organism is alive has little effect on how likely some of its cells might mutate into cancer. Instead, simply having more cells in your body does raise the specter of cancer--and does so enough that the benefits of telomerase expression, such as fast healing, weren't worth the cancer risk.

Gorbunova points out that these findings raise another, perhaps far more important question: What, then, does this mean for animals that are far larger than humans? If a 160-pound human must give up telomerase to thwart cancer, then what does a 250,000-pound whale have to do to keep its risk of cancer at bay? "It may be that whales have a cancer suppressant that we've never considered," says Gorbunova. "I'd like to find out what kind of telomerase expression they have, and find out what else they use to combat cancer."

Original Article

Deciphering Drosophila DNA

P(acman) -- a new method of introducing DNA into the genome of fruit
flies or Drosophila -- promises to transform the ability of scientists
to study the structure and function of virtually all the fly's genes,
and the method may be applicable to other frequently studied organisms
such as mice, said its Baylor College of Medicine developers in an
article in the current issue of the journal Science.

"P(acman) overcomes a key limitation of currently available methods
because it allows you to study large chunks of DNA in vivo," said Dr.
Hugo Bellen, professor of molecular and human genetics at Baylor College
of Medicine and director of the program in developmental biology. He is
also a Howard Hughes Medical Institute investigator. The new technique
allows researchers to study large genes and even gene complexes in the
fruit fly, which was not possible before.

P/phiC31 artificial chromosome for manipulation, or P(acman), combines
three recently developed technologies: a specially designed bacterial
artificial chromosome (BAC) that allows maintenance of large pieces of
DNA in bacteria, recombineering that allows the manipulation of large
pieces of DNA that can then be inserted into the genome of the fly at a
specific site using phiC31-mediated transgenesis.

It is a new technique with far-reaching promise, said Bellen.

P(acman) overcomes certain obstacles that have hampered research. It
allows the cloning of large pieces of DNA to be used to transform the
genome, and it permits that DNA to be inserted into specific places in
the genome. Bellen credits the report's first author, Koen J.T. Venken,
a graduate student in the BCM Program in Developmental Biology, with
putting the technologies together to come up with a new methodology in
the field.

Current technology has certain problems for researchers seeking to
understand the structure and function of genes, said Bellen. Often, when
scientists breed flies that lack a particular gene and then try to put
that gene back into the fly, it inserts itself randomly into the genetic
blueprint.

In some cases, it makes too much protein, and in others, too little. In
other instances, it may disrupt the message from another gene.

"You are really comparing apples and oranges when you do this," said
Bellen. The technique is also limited to small DNA chunks.

"Koen set out to develop a new transgenesis system using the three
techniques," said Bellen.

The bacterial artificial chromosome, or BAC, he used allows the
scientist to maintain large chunks of DNA in the bacteria, but it is
present in only one or few copies. However, the bacteria can be induced
to produce many copies of the DNA when needed.

Koen then integrated a technique called "recombineering" into the
strategy, which facilitates the scientist to clone large chunks of DNA
and subsequently allows them to make specific mutations anywhere he or
she wants in the gene.

The third technique allows the researcher to pinpoint where he or she
wants to the mutant gene to go in the genetic blueprint of the fly,
eliminating the apples-and-oranges problem. This third technique --
phiC31 -- works also in mouse and human cells, implying that this new
technique could be used in those cells as well.

Others who contributed to this report include Yuchun He, also of BCM,
and Dr. Roger A. Hoskins of Lawrence Berkeley National Laboratory in
Berkeley, California.

The work was supported by the National Institutes of Health and the
Howard Hughes Medical Institute.

Original Article
<http://www.sciencedaily.com/releases/2006/11/061130191541.htm>

Mitochondrial oxidant generation is involved in determining why females live longer than males.

Catholic University of Valencia, Spain.

Females live longer than males in many mammalian species, including humans. This natural phenomenon can be explained on the basis of the mitochondrial theory of aging. Mitochondria are a major source of free radicals in cells. Mitochondria from female rats generate half the amount of hydrogen peroxide than those of males and have higher levels of mitochondrial reduced glutathione. The latter is due to females behaving as double transgenic in over-expressing antioxidant enzymes. Estrogens bind to the estrogen receptors and subsequently activate the mitogen activated protein (MAP) kinase and nuclear factor kappa B (NFkappaB) signalling pathways, resulting in an upregulation of antioxidant enzymes. Moreover, the 16S rRNA expression, which decreases significantly with aging, is four times higher in mitochondria from females than in those from males of the same chronological age. On the contrary, the oxidative damage of mitochondrial DNA is fourfold higher in males than in females. Ovariectomy abolishes the gender differences between males and females and estrogen replacement rescues the effect of ovariectomy. The challenge for the future is to find molecules that have the beneficial effects of estradiol, but without its feminizing effects. Phytoestrogens or phytoestrogen-related molecules may be good candidates to meet this challenge.

Original Article